The latest advances in brain and central nervous system research were discussed at the 65th annual meeting of the American Academy of Neurology, held in San Diego, March 16-23, 2013.
Reports included results for clinical trials in amyotrophic lateral sclerosis (ALS) to test rasagiline, a drug currently approved by the U.S. Food and Drug Administration (FDA) to treat symptoms of Parkinson's disease; and the adult stem cell treatment NurOwn.
Interim results in an ongoing phase 2 trial for rasagiline in people with ALS show that the experimental therapy appears to be safe, with indications that it hits its intended biological target. Results were reported March 20, 2013, by neurologist Richard Barohn, chair of the department of neurology at the University of Kansas Medical Center.
Rasagiline, which belongs to a class of drugs called monoamine oxidase B inhibitors, has demonstrated neuroprotective properties in cell culture studies and in the SOD1 research mouse model of ALS.
The goals of the current 12-month study are to determine whether the drug is safe; if it has the potential to slow ALS disease progression; and if it has any effects on energy-producing subcomponents of cells called mitochondria. Mitochondrial dysfunction, as well as a cell-damaging process called oxidative stress, and stress-triggered programmed cell death called apoptosis, all have been proposed as causes of nerve cell death in ALS.
Participants in the open-label trial take 2 milligrams per day of rasagiline. Researchers are monitoring for adverse events and changes in the ALS Functional Rating Scale-Revised (ALSFRS-R), a widely used measure of functional ability in ALS. They also are assessing markers that can indicate oxidative stress, mitochondrial function and apoptosis.
Barohn reported that early results in the ongoing trial show improved mitochondrial function, an indication that the drug is reaching its intended target. In addition, researchers have observed increases in the levels of proteins called annexins, which serve as markers for apoptosis. So far, ALSFRS-R scores in participants have declined at a rate similar to the rate seen in “historical controls” (data from a similar group of ALS patients who were previously observed in other studies, and who did not receive the NurOwn treatment).
For more information, see Trial of Safety and Efficacy of Rasagiline in Patients with Amyotrophic Lateral Sclerosis (ALS), or enter NCT01232738 into the search box at ClinicalTrials.gov.
Barohn noted that a placebo-controlled phase 2 trial of rasagiline in ALS is under way in the United States. See Rasagiline in Subjects with Amyotrophic Lateral Sclerosis (ALS), or enter NCT01786603 in the search box at ClinicalTrials.gov. Another trial of the experimental therapy in ALS has just launched in Europe.
Final results from a small phase 1-2 clinical trial of the experimental NurOwn adult stem cell therapy in people with ALS indicate that the treatment appears to be safe, with no serious adverse events reported.
In addition, principal investigator Dimitrios Karussis reported "initial indications of clinical benefit"— a finding that the stem cells’ developer, BrainStorm Cell Therapeutics, says will require further confirmation in additional trials. Karussis reported the results March 20, 2013; they also are referenced in a March 21, 2013, BrainStorm press release.
Twelve people with ALS — six with early-stage disease, and six with more advanced ALS — participated in the trial, which took place at the Hadassah Medical Center in Jerusalem. Mesenchymal stem cells were taken from each participant's bone marrow, cultured into healthy cells capable of delivering neurotrophic factors (molecules that support nerve cells) and then readministered to the participants from whom they were taken. Although the trial was designed to assess safety, not functional effects of the stem cell treatment, investigators gathered information about motor function using the ALSFRS-R, and about respiratory function using Forced Vital Capacity (FVC) scores.
Karussis reported that in six patients who received an intrathecal (into the fluid around the spinal cord) injection of the cells, there was a significantly slower decline in overall clinical and respiratory function in the six months following treatment compared to the three months prior to treatment.
"ALS is a highly variable disease, with different patients progressing at different rates. As such, a report of improvement in only six patients, while exciting, is not proof that the treatment works," noted MDA Vice President of Research Jane Larkindale. "Such a result could come about by chance, so further trials are necessary to determine if this treatment can really slow progression."
BrainStorm currently is conducting a phase 2a dose-escalating trial of NurOwn stem cell therapy in ALS at Hadassah. For more information, see Autologous Cultured Mesenchymal Bone Marrow Stromal Cells Secreting Neurotrophic Factors (MSC-NTF), in Patients with Amyotrophic Lateral Sclerosis (ALS), or enter NCT01777646 into the search box at ClinicalTrials.gov.
The company also plans to launch a multicenter phase 2 trial of NurOwn in ALS at several sites in the United States.